rs1553706799

Variant names:

• chr3-47848247-G-A
• rs1553706799
• NM_138615.3:c.2354G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_138615.3(DHX30):​c.2354G>A​(p.Arg785His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R785C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX30 NM_138615.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.95

Genes affected

DHX30 (HGNC:16716): (DExH-box helicase 30) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The family member encoded by this gene is a mitochondrial nucleoid protein that associates with mitochondrial DNA. It has also been identified as a component of a transcriptional repressor complex that functions in retinal development, and it is required to optimize the function of the zinc-finger antiviral protein. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Helicase C-terminal (size 173) in uniprot entity DHX30_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_138615.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-47848246-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-47848247-G-A is Pathogenic according to our data. Variant chr3-47848247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47848247-G-A is described in Lovd as [Pathogenic]. Variant chr3-47848247-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX30	NM_138615.3	c.2354G>A	p.Arg785His	missense_variant	Exon 15 of 22	ENST00000445061.6	NP_619520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX30	ENST00000445061.6	c.2354G>A	p.Arg785His	missense_variant	Exon 15 of 22	1	NM_138615.3	ENSP00000405620.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with severe motor impairment and absent language Pathogenic:2

Jun 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHX30 c.2354G>A; p.Arg785His variant (rs1553706799 , ClinVar Variation ID 453272), as well as another variant at the same codon (c.2353C>T; p.Arg785Cys), have been reported in the de novo state in several individuals with NEDMIAL (Lessel 2017, Mannucci 2021, Ueda 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.952). Functional analyses of the p.Arg785His variant protein show impaired ATPase activity (Lessel 2017). Based on available information, the p.Arg785His variant is considered to be pathogenic. References: Lessel D et al. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. Am J Hum Genet. 2017 Nov 2;101(5):716-724. PMID: 29100085. Mannucci I et al. Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. Genome Med. 2021 May 21;13(1):90. PMID: 34020708. Ueda K et al. A Japanese adult and two girls with NEDMIAL caused by de novo missense variants in DHX30. Hum Genome Var. 2021 Jun 18;8(1):24. PMID: 34145223. -

Feb 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Dec 04, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a detrimental effect to protein function with reduced ATPase activity, a large number of cytoplasmic aggregates, and a reduced level of translation activity in HEK293T cells (Lessel et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28135719, 28191890, 34145223, 34020708, 29100085) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;H;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.84
MutPred		0.91		Loss of MoRF binding (P = 0.0126);.;Loss of MoRF binding (P = 0.0126);.;.;
MVP		0.90
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Varity_R		0.81
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553706799; hg19: chr3-47889737;